Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2001-05-09
2002-07-09
Geist, Gary (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C564S133000
Reexamination Certificate
active
06417388
ABSTRACT:
This application is a 371 of PCT1EP99/08740 filed Nov. 12, 1999.
1. Field of the Invention
The present invention relates to a process for preparing alkenyl-substituted bis(oxime ether) derivatives of the formula
where:
R
1
is unsubstituted C
1
-C
4
-alkyl or C
2
-C
4
-alkenyl-, C
2
-C
4
-alkynyl- or phenyl-substituted methyl;
R
2
,R
4
independently of one another are hydrogen or methyl;
R
3
,R
5
independently of one another are hydrogen or C
1
-C
4
-alkyl, trifluoromethyl or phenyl and
X is —C(═CHCH
3
)—COOCH
3
,
—C(═CHOCH
3
)—COOCH
3
,
—C(═NOCH
3
)—COOCH
3
,
—C(═NOCH
3
)—CONHCH
3
or
—N(OCH
3
)—COOCH
3
.
2. Background of the Invention
Alkenyl-substituted bis(oxime ether) derivatives of the formula I are described in the literature as interesting crop protection agents [cf. WO-A 95/21153, WO-A 95/21154, WO-A 96/16030 and WO-A 97/03057].
If the preparation processes described in these publications are applied specifically for synthesizing the alkenyl-substituted bis(oxime ether) derivatives of the formula I, the following difficulties are encountered:
The synthesis route shown in scheme 1, where the component A of the side chain and the component B which contains the pharmacophor are built up separately and only joined at the end, fails owing to the poor accessibility of component A. In the route shown in scheme A, for example, A is inaccessible because of the high ring-closure tendency of the precursors (cf. Tetrahedron Let. (1981) 2557).
It would furthermore be feasible to build up the side chain successively, starting from building block B, but this has the disadvantage that a large number of synthesis steps have to be performed successively. The expected total yield in such a process is only moderate, and the process is furthermore very tedious.
BRIEF SUMMARY OF THE INVENTION
It is an object of the present invention to provide an economical process which affords alkenyl-substituted bis(oxime ether) derivatives of the formula I in good yield starting from easily accessible starting materials.
We have found that this object is achieved by the process mentioned at the outset which comprises rearranging an alkenylalkyl derivative of the formula II,
in which the substituents R
1
to R
5
and X are as defined above, using a base and/or an isomerization catalyst.
DETAILED DESCRIPTION OF THE INVENTION
As shown in scheme 2, compounds of the formula II can be obtained in an advantageous manner starting from a bis(oxime) monoether of the formula IV and a benzyl derivative of the formula III.
The synthesis strategy shown in scheme 3 has been found to be particularly advantageous for compounds I having an oxime ether amide pharmacophor.
By alkylating compound IV with compound IIIa, the oxime ether ester IIa is obtained, which can be converted into the corresponding amide IIb. In the last step, the double bond is isomerized, giving the oxime ether amides of the formula I.
The process according to the invention is illustrated in more detail below.
The isomerization can be carried out in the presence of a base and/or an isomerization catalyst.
Suitable bases are metal hydrides, such as, for example, sodium hydride, or in particular alkali metal alkoxides, such as, for example, potassium tert-butoxide and preferably sodium methoxide or potassium methoxide.
In general, the base is employed in a molar ratio of from 1 to 4 and preferably from 1 to 2, based on the starting material II.
In addition or alternatively to the base, it is also possible to use an isomerization catalyst.
Suitable isomerization catalysts are, in particular, metallic palladium, or else palladium salts, such as palladium(II) chloride or palladium(II) acetate.
The isomerization catalyst is usually employed in a concentration of from 0.1 to 5 mol %.
Suitable solvents are, for example, aliphatic or aromatic hydrocarbons, such as toluene, xylene, heptane, aliphatic or cyclic ethers, such as 1,2-dimethoxyethane, tetrahydrofuran, dioxane or, in particular, polar aprotic solvents, such as acetonitrile, dimethyl sulfoxide, sulfolane, dimethyl formamide or dimethyl acetamide.
The reaction temperature is generally from 20 to 120° C. and preferably 20-40° C. In the case of the palladium-catalyzed reaction, higher temperatures of from 20 to 160° C. and preferably of from 80 to 140° C. are used.
The starting materials for the isomerization reaction are compounds of the formula II which are preferably prepared, as shown in scheme 2a, by route A) starting from a bis(oxime) monoether of the formula IV and a benzyl derivative of the formula III, or by route B) starting from an oxime ether of the formula V and a hydroxylamine of the formula VI.
The reaction A) is a nucleophilic substitution which can be 25 carried out under the customary reaction conditions. The benzyl compounds III are to be understood as compounds in which X is as defined in claim
1
and L
1
is a leaving group, such as halogen, acyloxy, alkylsulfonyloxy or arylsulfonyloxy and in particular chlorine or bromine. The substituents R
1
to R
5
of the bis(oxime) monoethers of the formula IV are as defined in claim
1
.
The reaction is expediently carried out in an inert solvent such as an ether, for example tetrahydrofuran or dioxane, or in a polar aprotic solvent, for example acetone, acetonitrile, dimethyl sulfoxide, sulfolane, dimethylformamide or dimethylacetamide.
The base which is employed is usually sodium carbonate or potassium carbonate, sodium hydride, sodium methoxide or a tertiary amine.
The reaction temperature is usually from −20 to 80° C.
The reaction can also be carried out in a two-phase system (for example dichloromethane/water) with the aid of a suitable phase-transfer catalyst.
Work-up of the reaction mixtures can be carried out, for example, by extraction.
The benzyl compounds of the formula III are disclosed in EP-A 348766, EP-A 363818 and EP-A 624155.
An advantageous route for preparing the starting materials IV and V is shown in scheme 4.
Step a):
Step a) is carried out similarly to the procedure described in U.S. Pat. No. 4,707,484.
Suitable for use as solvents are alcohols, such as, for example, methanol, and, in particular, water. In certain cases it may be advantageous to add solubilizers, such as, for example, surfactants or ethylene glycol.
Suitable bases are, in particular, sodium hydroxide and potassium hydroxide, which are usually employed in equimolar amounts or in an excess of up to 10 mol, based on the acetoacetic ester B. Nitrite is to be understood as meaning, for example, an alkali metal nitrite, in particular sodium nitrite, which is usually employed in equimolar amounts or in an excess of up to 30 mol %, based on the acetoacetic ester B.
In general, the reaction temperature should not exceed 40° C., since otherwise undesirable side reactions may occur. In water, the reaction is therefore preferably carried out at from −20 to 40° C., in particular at from 0 to 15° C.
After a period of from 10 to 48 hours, the reaction mixture usually becomes clear. It is then adjusted to a pH of from 0 to 5 and preferably from 1 to 3 using an acid, such as, for example, hydrochloric acid or sulfuric acid.
Work-up is carried out by customary methods, for example by extraction. For purification, the oxime can, for example, be converted into the corresponding salt using bases and reprecipitated using an acid.
The acetoacetic ester B used in the reaction can be prepared as described in Tetrahedron (1985)4633 (see scheme 5)
The alkenylalkyls of the formula A in which R
2
to R
5
are as defined in claim
1
and L
1
is halogen, acyloxy, alkylsulfonyloxy or arylsulfonyloxy are known, or they can be synthesized by processes known from the literature (Z. Org. Khim. (1997) 486; Bull. Chem. Soc. Jpn. (1980) 2586; J. Am. Chem. Soc. (1984) 2211; J. Am. Chem. Soc. (1960) 1886; DE-A 19 556 66; DE-A 33 173 56; EP-A 271212; Tetrahedron Let. (1986) 6027; Tetrahedron Let. (1994) 1371 and 2679; J. Fluorine Chem. (1997) 67; Helv. Chim. Acta (1951) 1514; Organomet. Chem. (1985) 395).
Step b):
The alkylation is usually
Bayer Herbert
Götz Norbert
Götz Roland
Grammenos Wassilios
Gypser Andreas
BASF - Aktiengesellschaft
Geist Gary
Keil & Weinkauf
Zucker Paul A.
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